High Throughput Drug Screens
The drug discovery process has traditionally been initiated by searching a very large chemical library for compounds that can affect disease characteristics, to identify “hit” compounds. Hits are further tested and developed into leads. Lead compounds in turn are further refined, generally using medicinal chemistry, and tested with view to enter clinical trials and finally developing a drug for use in man.
High throughput screening methods for hits are generally based on in vitro cell culture, biochemical assays or receptor binding assays. Hit compounds identified in these assays need much in the way of further testing and refinement for in vivo use. Even in vitro cell culture assays, which are less artificial than biochemical or receptor binding assays, often fail to reliably indicate, for example, whether a compound will be toxic in vivo. The behavior of individual cells in culture can differ dramatically from the behavior of tissues in response to the same agent. Cells in culture often lack the nutrients, cell-cell contacts, basal membrane contacts, cell-cell signaling events, and physical forces that influence their behavior in vivo. Furthermore, immortalized cell lines often exhibit metabolisms and signal transduction events that vary markedly from the primary cell lines from which they are derived. As a result, the vast majority of hit compounds identified using traditional in vitro high throughput screening methods never become drugs, even after extensive medicinal chemistry optimization efforts are applied (Keserü and Makara, 2006).
In Vivo Drug Screens
Recently, there has been an increased interest in using whole animals to screen large chemical libraries. Such screens could potentially yield hits in a context in which relevant biological systems are present and functioning together in an intact organism. Though screens in mammalian models such as mice and rats are not practical due to the time and costs that would invariably be involved, smaller organisms whose biology has already been established to be relevant with respect to human disease are attractive candidates for use in drug discovery.
Drosophila melanogaster as a Tool for Drug Screens
The fruit fly (D. melanogaster) is a model organism which has been applied to the study of human genetics and development due to its small size, short generation time, prolific reproduction, and genetic tractability (Beir E., 2005). D. melanogaster's usefulness as a genetic tool has facilitated the development of high throughput in vivo screens for chemical suppressors of pathological phenotypes in genetically modified strains (e.g., U.S. Pat. No. 6,316,690). While such screens may provide lead compounds which have been identified in an in vivo context, they rely on flies with artificial genetic backgrounds that often do not develop or behave like wild-type flies. In addition, D. melanogaster is an invertebrate, and as a result many aspects of its development, metabolism, and morphology can be markedly different from those of mammals.